Donor-specific transplant tolerance by immune reset

About This Grant

ABSTRACT Immune tolerance remains the goal of allogeneic human organ transplantation in order to achieve safe and long-term transplant function. If achieved, tolerance would reduce the need for retransplants by substantially prolonging the durability of organ transplants and preventing immunologic rejection. This elusive goal is the aim of this proposal, which is based on observations that T regulatory cells (Treg) are able to downregulate the peripheral immune response to organ transplants in animal models and humans. Harnessing such Tregs for the purposes of donor-specific tolerance may be possible using a combination of recently developed novel approaches. These approaches include administering an IL-2 mutein (mIL-2) to promote Tregs in combination with drugs such as rapamycin, anti-CD154 mAb, IL-6 receptor blockade (Tocilizumab) and complement blockade (anti-C3). The need for donor-specificity to tolerance can be substantially enhanced by the exposure of the organ transplant recipient to chemically treated (ECDI) donor B cells, as well as the administration of CAR-Tregs that confer regulation to a specific donor MHC antigen. Each of these technologies is available to us to apply to what is likely the most relevant and feasible animal model that accurately simulates human biology: namely, a rhesus monkey kidney allograft model. We have considerable experience using this model to develop novel immunotherapies that have been successfully introduced into the clinical transplant arena. Examples include T cell depleting therapy, co-stimulation blockade, and desensitization to MHC. We propose to use a combination of Treg promoting strategies in combination with ECDI-treated donor B cells and CAR- Tregs in controlled experiments and with state-of-the-art mechanistic support to define the immunologic impact of each therapy. These data would guide the rational development of a tolerance-inducing strategy and monitoring tools that would be feasible to apply to an initial human kidney transplant trial of Treg-based peripheral tolerance.